original article Wien Klin Wochenschr DOI 10.1007/s00508-015-0798-3
The role of intraluminal thrombus formation for expansion of abdominal aortic aneurysms Sophie Brunner-Ziegler · Alexandra Hammer · Daniela Seidinger · Andrea Willfort-Ehringer · Renate Koppensteiner · Sabine Steiner
Received: 26 September 2014 / Accepted: 21 April 2015 © Springer-Verlag Wien 2015
Summary Background Though the pathophysiology of initiation, formation, and expansion of abdominal aortic aneurysm (AAA) has been intensely researched, the distinct mechanisms driving these processes still remain unclear. In particular, human studies on predictors of AAA progression as a major determinant of rupture risk are scarce. Methods All consecutive abdominal aortic ultrasound sonographic examinations performed at the duplex laboratory of the Division of Angiology of the Medical University of Vienna between 1999 and 2012 were reviewed. Patients with repeated measurements of the infrarenal aortic diameter, who had no prior AAA repair were included. Detailed informations on AAA, including length, anterior-posterior and transversal measurements of diameter, and intraluminal thrombus formation/size were obtained from ultrasound examination; patients’ comorbidities, cardiovascular risk factors, and medications were obtained from outpatient charts. The expansion rate of AAA in relation to intraluminal thrombus size, gender, age, comorbidities, cardiovascular risk factors, and pharmacotherapy was evaluated. Independent predictors of AAA growth were identified through mixed effects models. Results In total, 166 patients (123 men and 43 women, mean age 68 ± 9 years) were included. Patients were followed over a mean period of 1.4 ± 1.2 years with a mean number of follow-up investigations of 4.4 ± 2.7. Overall, mean maximum AAA diameter at baseline was 37.4 ± 8.2 mm. The average expansion rate of AAA diamDr. S. Brunner-Ziegler, MPH () · A. Hammer · D. Seidinger · A. Willfort-Ehringer · R. Koppensteiner · S. Steiner Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria e-mail: [email protected]
13
eter throughout the follow-up period was 2.0 mm per year (95 % confidence interval: 1.6–2.4). At initial investigation, intraluminal thrombus formation was present in 56.6 % of all patients. AAA diameter at baseline, time of follow-up as well as presence and size of intraluminal thrombus formation were identified as independent predictors of AAA expansion rate. Importantly, gender and presence of cardiovascular risk factors were not associated with AAA progression rate. Conclusions Intraluminal thrombus formation seems to be a key determinant for progression of AAA diameter. Further prospective longitudinal studies are warranted to confirm the potential impact of thrombus formation on AAA development and its implication on monitoring and treatment decisions in patients with AAA. Keywords Abdominal aortic aneurysm · Intraluminal thrombus · Yearly growth rate · Atherosclerotic risk factors
Introduction Abdominal aortic aneurysm (AAA) is commonly defined as an irreversible and usually progressive widening of all layers of the abdominal aortic arterial wall with a diameter of 3 or more centimeters. Even aortic ectasias with a diameter of at least 2.5 cm have been linked to a high likelihood of significant size progression within a 5-year follow-up period [1]. The prevalence of AAA has been estimated on the basis of several large population screening studies showing substantial variation depending on age, gender, region, and smoking rates. In the Aneurysm Detection and Management (ADAM) Study, the largest study so far comprising 126,196 American veterans aged 50–79 years, an infrarenal aortic diameter greater than 3 cm was found in 4.2 % of participants [2]. In the Multicentre Aneurysm Screening Study (MASS) on 27,147 men between 65 and 74 years, the prevalence rate
The role of intraluminal thrombus formation for expansion of abdominal aortic aneurysms
1
original article
of AAA was 4.9 % [3]. Recently, the observed reduction of smoking rates has been linked to a lower than expected prevalence of AAA (1.7 %) in Swedish 65-year-old men [4]. Importantly, rupture as the major complication of AAA is usually fatal, and therefore surveillance of known AAA by duplex ultrasound according to recommended guidelines is mandatory [5]. The risk of rupture of an AAA smaller than 4 cm is below 2 % per year, but increases exponentially once a diameter of 5 cm is passed. From a clinical point of view, the main risk factors for AAA initiation and formation include male gender, advanced age, cigarette smoking, positive family history, and presence of atherosclerosis [6–10]. However, determinants of AAA progression have been poorly and sometimes controversially defined, so far. In particular, most human studies on predictors of AAA progression as a major determinant of rupture risk were performed several years ago but the importance of various risk factors might have changed due to evolving treatment strategies for cardiovascular risk factors, such as the widespread prescription of statins and continuing improvement of arterial hypertension control. The average rate of growth of an AAA is 2–3 mm per year but can vary substantially between individuals [11]. To determine the intervals between surveillance investigations, traditionally the initial diameter of AAA is used, as it has been proven an accurate and independent predictor for increased AAA expansion rate [8]. However, during the past years concern has been raised on using the initial diameter alone in prediction of AAA expansion, hypothesizing that endogenous and also environmental factors could impact the inter- and intra-patient highly variable growth rate of AAAs [11]. In this context, female gender and cigarette consumption have been found to be independent predictors for both, increased AAA growth- and rupture rate [12, 13]. Golledge et al. implied a protective role of serum high-density lipoprotein levels in patients with AAA in terms of delaying AAA progression [14]. While the occurrence of AAA is positively correlated with cardiovascular risk factors and disease, a reduced incidence and delayed progression for abdominal but also thoracic aortic aneurysms have been described in correlation to diabetes [14, 15]. Furthermore, the presence of generalized atherosclerosis and aortic calcification has been associated with slower AAA expansion [16–18]. Besides, the shape of the aneurysm, the presence of intraluminal thrombus and characteristics of the wall tissue are assumed to be involved in AAA evolution. Albeit mathematical models have investigated the impact of wall strength and wall shear stress on AAA progression, clinical studies on such parameters are rare and there is still a lack of consensus regarding its impact on AAA evolution and rupture risk in humans [17, 19–22]. In this mono-center retrospective cohort study, we aimed to study AAA expansion rates in patients receiving contemporary treatments for cardiovascular risk factor control and to identify predictors of AAA progression.
Patients and methods All consecutive abdominal aortic ultrasound sonographic examinations of the infrarenal aortic diameter performed at the duplex laboratory of the Division of Angiology of the Medical University of Vienna between 1999 and 2012 were retrospectively reviewed. Patients with suspected AAA and at least one follow-up investigation without prior AAA repair were included for analysis. While AAA is usually defined as dilation of the abdominal aortic artery of ≥ 30 mm, we used a definition of enlargement ≥ 25 mm for study inclusion since aortic ectasia has been linked to a high likelihood of significant progression within a 5-year follow-up period [1]. All informations were obtained from the outpatient charts. Each patient visit comprised of an ultrasound examination, which was performed by a trained and skilled sonographer, measuring the length and the maximum anterior-posterior and transversal diameter of the ectatic arterial segment. If intraluminal thrombus formation was present, the maximum extent was recorded. According to a standardized protocol, at our department in each patient the following parameters were recorded at first presentation: medical history including cardiovascular risk factors and prior diagnosis of atherosclerotic diseases, comorbidities (chronic obstructive pulmonary disease, neoplastic disorder, and chronic kidney disease), AAA symptoms, and prior pharmacotherapy. Each patient underwent clinical examination and optionally additional vascular examinations (ankle brachial index (ABI), carotid ultrasound) if requested by the treating physician. Coronary heart disease was defined as a history of myocardial infarction, angina, and/or coronary revascularization. Peripheral artery disease (PAD) was defined as ABI below 0.9 and/or history of peripheral revascularization (endovascular intervention or bypass surgery). Cerebrovascular disease was defined as the presence of hemodynamic relevant atherosclerotic plaques of the supra-aortic extracerebral carotid arteries and/or a history of stroke or transient ischemic attack. Arterial hypertension was defined as either treatment with antihypertensives or repeated arterial blood pressure measurements of systolic ≥ 140 mmHg and/or diastolic ≥ 90 mmHg. Cigarette smoking was classified as never smoking, current smoking, and former smoking. Hyperlipidemia was defined as either elevated fasting blood concentrations of total cholesterols of > 200 mg/dl and/or statin intake. The follow-up intervals were at the discretion of the treating physician and not pre-defined by the study protocol, as this is a retrospective study.
Statistical analysis Continuous data are presented as mean ± standard deviation; categorial data are given as number (percentage). To compare groups unpaired t-test or chi-square test was used as appropriate.
2 The role of intraluminal thrombus formation for expansion of abdominal aortic aneurysms
13
original article
Mixed effects linear regression models with random intercept and slope were performed to evaluate factors that may influence AAA growth rates using the SAS procedure Proc mixed. Baseline AAA diameter, patient characteristics (age, gender, body mass index, comorbidities, cardiovascular risk factors), pharmacotherapy, and presence of thrombus formation were investigated as potential independent factors associated with AAA growth and were considered statistically significant at p
The role of intraluminal thrombus formation for expansion of abdominal aortic aneurysms Sophie Brunner-Ziegler · Alexandra Hammer · Daniela Seidinger · Andrea Willfort-Ehringer · Renate Koppensteiner · Sabine Steiner
Received: 26 September 2014 / Accepted: 21 April 2015 © Springer-Verlag Wien 2015
Summary Background Though the pathophysiology of initiation, formation, and expansion of abdominal aortic aneurysm (AAA) has been intensely researched, the distinct mechanisms driving these processes still remain unclear. In particular, human studies on predictors of AAA progression as a major determinant of rupture risk are scarce. Methods All consecutive abdominal aortic ultrasound sonographic examinations performed at the duplex laboratory of the Division of Angiology of the Medical University of Vienna between 1999 and 2012 were reviewed. Patients with repeated measurements of the infrarenal aortic diameter, who had no prior AAA repair were included. Detailed informations on AAA, including length, anterior-posterior and transversal measurements of diameter, and intraluminal thrombus formation/size were obtained from ultrasound examination; patients’ comorbidities, cardiovascular risk factors, and medications were obtained from outpatient charts. The expansion rate of AAA in relation to intraluminal thrombus size, gender, age, comorbidities, cardiovascular risk factors, and pharmacotherapy was evaluated. Independent predictors of AAA growth were identified through mixed effects models. Results In total, 166 patients (123 men and 43 women, mean age 68 ± 9 years) were included. Patients were followed over a mean period of 1.4 ± 1.2 years with a mean number of follow-up investigations of 4.4 ± 2.7. Overall, mean maximum AAA diameter at baseline was 37.4 ± 8.2 mm. The average expansion rate of AAA diamDr. S. Brunner-Ziegler, MPH () · A. Hammer · D. Seidinger · A. Willfort-Ehringer · R. Koppensteiner · S. Steiner Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria e-mail: [email protected]
13
eter throughout the follow-up period was 2.0 mm per year (95 % confidence interval: 1.6–2.4). At initial investigation, intraluminal thrombus formation was present in 56.6 % of all patients. AAA diameter at baseline, time of follow-up as well as presence and size of intraluminal thrombus formation were identified as independent predictors of AAA expansion rate. Importantly, gender and presence of cardiovascular risk factors were not associated with AAA progression rate. Conclusions Intraluminal thrombus formation seems to be a key determinant for progression of AAA diameter. Further prospective longitudinal studies are warranted to confirm the potential impact of thrombus formation on AAA development and its implication on monitoring and treatment decisions in patients with AAA. Keywords Abdominal aortic aneurysm · Intraluminal thrombus · Yearly growth rate · Atherosclerotic risk factors
Introduction Abdominal aortic aneurysm (AAA) is commonly defined as an irreversible and usually progressive widening of all layers of the abdominal aortic arterial wall with a diameter of 3 or more centimeters. Even aortic ectasias with a diameter of at least 2.5 cm have been linked to a high likelihood of significant size progression within a 5-year follow-up period [1]. The prevalence of AAA has been estimated on the basis of several large population screening studies showing substantial variation depending on age, gender, region, and smoking rates. In the Aneurysm Detection and Management (ADAM) Study, the largest study so far comprising 126,196 American veterans aged 50–79 years, an infrarenal aortic diameter greater than 3 cm was found in 4.2 % of participants [2]. In the Multicentre Aneurysm Screening Study (MASS) on 27,147 men between 65 and 74 years, the prevalence rate
The role of intraluminal thrombus formation for expansion of abdominal aortic aneurysms
1
original article
of AAA was 4.9 % [3]. Recently, the observed reduction of smoking rates has been linked to a lower than expected prevalence of AAA (1.7 %) in Swedish 65-year-old men [4]. Importantly, rupture as the major complication of AAA is usually fatal, and therefore surveillance of known AAA by duplex ultrasound according to recommended guidelines is mandatory [5]. The risk of rupture of an AAA smaller than 4 cm is below 2 % per year, but increases exponentially once a diameter of 5 cm is passed. From a clinical point of view, the main risk factors for AAA initiation and formation include male gender, advanced age, cigarette smoking, positive family history, and presence of atherosclerosis [6–10]. However, determinants of AAA progression have been poorly and sometimes controversially defined, so far. In particular, most human studies on predictors of AAA progression as a major determinant of rupture risk were performed several years ago but the importance of various risk factors might have changed due to evolving treatment strategies for cardiovascular risk factors, such as the widespread prescription of statins and continuing improvement of arterial hypertension control. The average rate of growth of an AAA is 2–3 mm per year but can vary substantially between individuals [11]. To determine the intervals between surveillance investigations, traditionally the initial diameter of AAA is used, as it has been proven an accurate and independent predictor for increased AAA expansion rate [8]. However, during the past years concern has been raised on using the initial diameter alone in prediction of AAA expansion, hypothesizing that endogenous and also environmental factors could impact the inter- and intra-patient highly variable growth rate of AAAs [11]. In this context, female gender and cigarette consumption have been found to be independent predictors for both, increased AAA growth- and rupture rate [12, 13]. Golledge et al. implied a protective role of serum high-density lipoprotein levels in patients with AAA in terms of delaying AAA progression [14]. While the occurrence of AAA is positively correlated with cardiovascular risk factors and disease, a reduced incidence and delayed progression for abdominal but also thoracic aortic aneurysms have been described in correlation to diabetes [14, 15]. Furthermore, the presence of generalized atherosclerosis and aortic calcification has been associated with slower AAA expansion [16–18]. Besides, the shape of the aneurysm, the presence of intraluminal thrombus and characteristics of the wall tissue are assumed to be involved in AAA evolution. Albeit mathematical models have investigated the impact of wall strength and wall shear stress on AAA progression, clinical studies on such parameters are rare and there is still a lack of consensus regarding its impact on AAA evolution and rupture risk in humans [17, 19–22]. In this mono-center retrospective cohort study, we aimed to study AAA expansion rates in patients receiving contemporary treatments for cardiovascular risk factor control and to identify predictors of AAA progression.
Patients and methods All consecutive abdominal aortic ultrasound sonographic examinations of the infrarenal aortic diameter performed at the duplex laboratory of the Division of Angiology of the Medical University of Vienna between 1999 and 2012 were retrospectively reviewed. Patients with suspected AAA and at least one follow-up investigation without prior AAA repair were included for analysis. While AAA is usually defined as dilation of the abdominal aortic artery of ≥ 30 mm, we used a definition of enlargement ≥ 25 mm for study inclusion since aortic ectasia has been linked to a high likelihood of significant progression within a 5-year follow-up period [1]. All informations were obtained from the outpatient charts. Each patient visit comprised of an ultrasound examination, which was performed by a trained and skilled sonographer, measuring the length and the maximum anterior-posterior and transversal diameter of the ectatic arterial segment. If intraluminal thrombus formation was present, the maximum extent was recorded. According to a standardized protocol, at our department in each patient the following parameters were recorded at first presentation: medical history including cardiovascular risk factors and prior diagnosis of atherosclerotic diseases, comorbidities (chronic obstructive pulmonary disease, neoplastic disorder, and chronic kidney disease), AAA symptoms, and prior pharmacotherapy. Each patient underwent clinical examination and optionally additional vascular examinations (ankle brachial index (ABI), carotid ultrasound) if requested by the treating physician. Coronary heart disease was defined as a history of myocardial infarction, angina, and/or coronary revascularization. Peripheral artery disease (PAD) was defined as ABI below 0.9 and/or history of peripheral revascularization (endovascular intervention or bypass surgery). Cerebrovascular disease was defined as the presence of hemodynamic relevant atherosclerotic plaques of the supra-aortic extracerebral carotid arteries and/or a history of stroke or transient ischemic attack. Arterial hypertension was defined as either treatment with antihypertensives or repeated arterial blood pressure measurements of systolic ≥ 140 mmHg and/or diastolic ≥ 90 mmHg. Cigarette smoking was classified as never smoking, current smoking, and former smoking. Hyperlipidemia was defined as either elevated fasting blood concentrations of total cholesterols of > 200 mg/dl and/or statin intake. The follow-up intervals were at the discretion of the treating physician and not pre-defined by the study protocol, as this is a retrospective study.
Statistical analysis Continuous data are presented as mean ± standard deviation; categorial data are given as number (percentage). To compare groups unpaired t-test or chi-square test was used as appropriate.
2 The role of intraluminal thrombus formation for expansion of abdominal aortic aneurysms
13
original article
Mixed effects linear regression models with random intercept and slope were performed to evaluate factors that may influence AAA growth rates using the SAS procedure Proc mixed. Baseline AAA diameter, patient characteristics (age, gender, body mass index, comorbidities, cardiovascular risk factors), pharmacotherapy, and presence of thrombus formation were investigated as potential independent factors associated with AAA growth and were considered statistically significant at p
